Download Dorsal–ventral patterning: a view from the top - ICB-USP

Dorsal–ventral patterning: a view from the top
BinQuan Zhuang and Shanthini Sockanathan
The generation of dorsal interneurons in the spinal cord is
dependent upon specific signaling pathways and the
subsequent establishment of progenitor domains mediated by
cross-repressive interactions of different groups of
transcription factors. These events lead to the implementation
of specific differentiation programs that direct the development
of distinct dorsal interneuron subtypes. Recent studies have
taken advantage of complementary gain and loss-of-function
studies in the chick and mouse to clarify the in vivo roles of
transforming growth factor b signaling, basic helix-loop-helix
and homeodomain transcription factors in dorsal interneuron
development. The challenge now lies in identifying the precise
molecular mechanisms involved and applying these insights to
understanding how more ventrally located dorsal interneurons
are specified.
Addresses
Preclinical Teaching Building, 1004, Department of Neuroscience, Johns
Hopkins University School of Medicine, 725 North Wolfe Street,
Baltimore, MD 21205, USA
dermal structures, whereas the roofplate is generated
dorsally by signals from the overlying ectoderm [2,5].
Both of these structures secrete molecules that act non
cell-autonomously to regulate multiple aspects of neuronal development. The floorplate generates a gradient of
sonic hedgehog (shh) that is interpreted to establish five
progenitor domains (p0–p3, pMN; p, progenitor; MN,
motor neuron) that express different combinations of
Class I and Class II homeodomain (HD) transcription
factors. The sharp boundaries between these domains are
established and maintained through selective crossrepressive interactions between complementary pairs of
Class I and II proteins. Progenitor cells subsequently
differentiate into molecularly distinct neuronal subtypes
(V0–V3, MN) and the coordination of neuronal subtype
specification and differentiation is regulated by HD transcription factors and basic helix–loop–helix (bHLH) proteins. Thus, the initial location of a cell along the dorsal–
ventral axis is a crucial component for the acquisition of
neuronal identity.
Corresponding author: Sockanathan, Shanthini ([email protected])
Current Opinion in Neurobiology 2006, 16:20–24
This review comes from a themed issue on
Development
Edited by Anirvan Ghosh and Christine E Holt
Available online 7th December 2005
0959-4388/$ – see front matter
# 2005 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.conb.2005.11.001
Introduction
The nervous system is a complex network of interacting
neural circuits that utilize a vast and diverse array of
neurons to integrate and disseminate information. In
vertebrates, many of the specialized characteristics
unique to different groups of neurons are acquired during
embryogenesis [1,2]. Much of our understanding of how
this occurs comes from studies of cell fate specification in
the developing spinal cord [2–4].
A considerable amount of work in several organisms, in
particular the chick and mouse, has led to the current
model of how different spinal neurons are generated in
vertebrates (Figure 1a) [2–4]. Initially, two morphologically distinct signaling centers are established at opposite
ends of the dorsal–ventral axis of the developing neural
tube. The floorplate is induced ventrally by axial mesoCurrent Opinion in Neurobiology 2006, 16:20–24
How neuronal diversity is achieved dorsally is not as well
understood. Insight gleaned from ventral patterning studies has helped to provide a framework to investigate how
dorsal progenitors and dorsal interneurons (dI) are specified in the neural tube. In this review, we discuss studies
during the past two years that have exploited in vivo
functional assays in the mouse and chick that help us
understand how different classes of dIs are generated
during embryonic development.
Several extrinsic signals are necessary
for dI specification
DIs are divided into six early born (dI1–6) and two late
born (dILA and dILB) neuronal subtypes based on their
birthdate, dorso–ventral position and HD protein expression profile (Figure 1b) [5]. They are broadly categorized
into two groups; Class A neurons consist of the dorsal most
dI1–3 subtypes and rely on roofplate-derived signals for
their development, whereas the more ventrally located
Class B neurons comprise dI4–6 and dILA/B subtypes and
their generation is dependent on alternative sources of
signals [6–10]. The roofplate produces at least two major
classes of signaling molecules: members of the transforming growth factor b (TGFb) family (activin, bone morphogenetic protein 4 [BMP4], BMP5, BMP7, dorsalin1
and growth differentiation factor7 [GDF7]) and winglessrelated mouse mammary tumor virus integration site
proteins (Wnt1 and Wnt3a) [6,9–11]. Loss-of-function
studies in the mouse have shown that GDF7 and Wnt
proteins are required for generating Class A neurons
but not Class B neurons, which is consistent with the
www.sciencedirect.com
Dorsal–ventral patterning Zhuang and Sockanathan 21
Figure 1
Neuronal cell types in the spinal cord. (a) In the ventral spinal cord, five progenitor domains (p0–3 and pMN) located in the ventricular zone generate
five distinct mature neuronal subtypes (V0–3 and MN) occupying the mantle zone. The boundaries of progenitor domains are maintained and refined by
selective cross repression between pairs of Class I and Class II homeodomain (HD) transcription factors. Shown here are two examples. Class I HD
proteins Pax6 and Dbx2 cross repress complementary Class II HD proteins Nkx2.2 and Nkx6.1, respectively. (b) In the dorsal spinal cord, six
progenitor domains (dp1–6) generate six early born (dI1–6) and two late born (dILA and dILB) dorsal interneurons. These eight subtypes are
categorized into two classes: roofplate-dependent Class A (dI1–3) and roofplate-independent Class B (dI4–6 and dILA/B) neurons. Unlike the
ventral spinal cord, basic helix–loop–helix (bHLH) transcription factors have a predominant role in patterning progenitor domains. Cross repression
between Math1, Ngn1 and Mash1 are essential for delineating boundaries of Class A dorsal progenitors (dp1–3). Other progenitor markers
are also shown: Ngn2 in dp2–5, Olig3 in dp1–3, Gsh2 in dp3–5 and Gsh1 in dp4–5. Abbreviations: FP, floorplate; RP, roofplate.
development of Class B neurons being independent from
roofplate-derived signals [6,9]. However, recent work
suggests that Wnts might have a mitogenic function
rather than a role in patterning [12,13].
Investigating the role of BMPs in dI generation by similar
means has not been as informative because of the problems of redundancy and of early lethal phenotypes [14];
however, alternative approaches have recently shed light
on how BMPs contribute to dI development in vivo. In
the chick, overexpression of constitutively active BMP
type 1 receptors (Bmpr1) by in ovo electroporation was
found to increase dI1 progenitors and dI1 interneurons at
the expense of other classes of dIs, in a process that might
be mediated by the transcription factor Msx3 [15].
Lower amounts of activated BMP receptor, however,
induced a more ventral dI3 subtype [16], consistent with
a requirement for graded BMP signaling in Class A
neuronal generation. Conversely, inhibition of BMP signaling by expression of the BMP antagonist noggin or by
neural tube-specific inactivation of both BMPr1a and
BMPr1b receptors resulted in reduced numbers of dI1
and dI2 neurons, underscoring a role for BMPs in Class A
neuronal development [13,17]. Interestingly, dI3 neurons are still generated in the receptor knockout mice,
raising the possibility that other signals might operate to
impose dI3 subtype identities. Given that activin signaling can promote dI3 interneuron differentiation independently of BMPs, one possibility is that both BMPs and
activin signaling might contribute to the specification of
www.sciencedirect.com
dI3 neurons in vivo [18]. This is consistent with the
observation that short interfering RNA (siRNA)-dependent knockdown of Smad4, which can mediate both BMP4
and activin signaling, results in the decrease of dI3 neuronal subtypes [13]. Taken together, these studies
demonstrate a function for BMPs in Class A neuronal
generation. However, they also highlight the inherent
complexity of the signaling mechanisms involved in roofplate-dependent specification of Class A neurons, which is
in stark contrast to the central role occupied by floorplatederived shh in patterning the ventral spinal cord [2–4].
The signals involved in Class B neuronal development
remain undetermined. Class B neurons are prevented
from developing in the dorsal most regions of the spinal
cord by the action of TGFb signaling [16,19,20]. This has
provoked discussion as to whether a Class B fate is a
default state in the dorsal spinal cord or if instructive
signals are required for Class B neuronal specification.
What other molecules might contribute to dI generation?
Candidates include retinoic acid (RA), which is required
for the generation and specification of V0 and V1 ventral
interneurons that neighbor the Class B neurons and of
more ventrally located motor neurons [21–25]. Studies of
vitamin A deficient quails show a reduction of dorsal and
ventral markers, suggesting a role for RA signaling in
dorsal patterning. However, the basis for the RA-dependent dorsal phenotypes remains unclear and further
investigation is required to define specific roles for RA
signaling in dI generation [26].
Current Opinion in Neurobiology 2006, 16:20–24
22 Development
Factors mediating Class A versus Class B
differentiation
An obvious first step in deciphering the molecular
mechanisms that direct the development of Class A
and Class B neurons is in the identification and characterization of molecules that are differentially expressed in
these neuronal groups. Previous studies have shown that
the HD protein Lbx1 is expressed specifically in postmitotic Class B neurons. Loss and gain of function studies
in the mouse and chick, respectively, indicate that Lbx1
acts dually to repress Class A neuronal specification
programs while promoting Class B fates in postmitotic
dIs [19,20]. These studies have led to the idea that dIs
remain plastic in their fates even after they have exited
the cell cycle, a property that is shared by ventrally
located motor neurons that depend on HD proteins for
their specification [2]. They also raise the possibility that
similar postmitotic determinants might exist for Class A
neurons, although such factors have not been identified to
date. Furthermore, are there factors that act earlier to
distinguish progenitor cells that will give rise to Class A
and Class B neurons? Such factors have not been isolated
for Class B progenitors but a recent study has identified a
gene that imposes Class A character on dorsal cells [27].
Expression analyses combined with genetic lineage tracing experiments demonstrate that the bHLH protein
Olig3 is expressed in dorsal progenitors that give rise to all
dI1–3 Class A neurons (Figure 1b). Targeted deletion of
Olig3 in the mouse results in severe deficits in Class A
neurons that are accompanied by the dorsal generation of
ectopic dI4-like neurons (Figure 2a,b) [27]. These
findings suggest that Olig3 is required for Class A neuronal generation and might function by suppressing the
emergence of Class B neurons. Analysis of Lbx1 and
Olig3 double mutants showed rescue of dI1 and dI2
but not dI3 neurons, suggesting that Olig3 does not solely
suppress Class B differentiation programs dorsally, but
can direct the generation of dI3 subtypes. Consistent with
this hypothesis, overexpression of Olig3 in the chick
dorsal spinal cord resulted in an increase of dI3s over
other Class A neuronal subtypes and at the expense of
Class B neurons [27].
How might Olig3 function in progenitors to influence the
generation of Class A neurons? Dorsal progenitors can be
partly classified by the non-overlapping expression of
bHLH transcription factors that act as crucial determinants of dI identity; specifically, Math1 expression marks
progenitors that will give rise to dI1 subtypes [28],
whereas expression of Ngn1/2 and Mash1 delineate progenitor domains that will generate dI2 and dI3–5 subtypes, respectively (Figure 1b) [29]. In Olig3 mutants,
expression of Math1, Ngn1 and Ngn2 was reduced in
progenitors located within the dI1 and dI2 domains, thus
explaining the dearth of dI1 and dI2 subtypes in these
mice (Figure 2a,b). Overexpression of Mash1 and Olig3
together greatly increases the number of dI3s compared
with Mash1 or Olig3 overexpression alone. This suggests
that Olig3 and Mash1 function together in progenitor
cells to impose subsequent dI3 fates [27], but whether
these effects are additive or synergistic in nature remains
unclear. Furthermore, ectopic dI3s are generated predominantly in the dorsal rather than the ventral spinal cord,
indicating that other signals are acting to constrain their
development dorsally.
bHLH and HD proteins in dI3–dI5 generation
Superimposed upon the regulatory mechanisms specifying Class A and Class B neuronal fates are distinct dI
Figure 2
Phenotypes pertaining to dorsal interneuron (dI) development in wild type and knockout mouse embryos. (a) In wild type spinal cord,
six early dI subtypes are generated. (b) In Olig3 mutants, dI1 neurons are reduced and dI2–3 neurons are mis-specified to a dI4-like identity (*),
whereas Class B dI interneurons remain unaffected. (c) In Mash1 mutants, dI3 neurons are dramatically reduced and dI5 neurons are absent,
whereas neighboring dI2 and dI4 neurons are increased. (d) In Gsh2 mutants, dI3 neurons are selectively lost, whereas dI2 and dI4 neurons are
expanded.
Current Opinion in Neurobiology 2006, 16:20–24
www.sciencedirect.com
Dorsal–ventral patterning Zhuang and Sockanathan 23
differentiation programs controlled by bHLH determinants that are regionally expressed in progenitors
(Figure 1b). Cross-repressive interactions between these
proteins are thought to refine dorsal progenitor domains,
reminiscent of the HD protein interactions that operate
ventrally [5].
The position of dorsal progenitors along the dorsal–ventral axis largely correlates with the differentiation of
specific dI subtypes before their migration, as in the case
of dI1 and dI2 neurons [5]. Thus, dI3–dI5s have been
largely assumed to derive from Mash1+ progenitor cells.
However, analyses of Mash1 knockout mice reveal a
requirement for Mash1 in the development of dI3 and
dI5 but not dI4 neurons (Figure 2c) [30,31]. Lineage
studies show that dI3 and dI5 progenitors express Mash1
but that dI4 progenitors express low to undetectable
levels of the protein, underscoring the value of such
analyses in assigning progenitor–neuron relationships
[30]. Consistent with a role for Mash1 in dI3 and dI5
specification, overexpression of Mash1 in the chick by in
ovo electroporation resulted in increased levels of dI3 and
dI5 subtypes at the expense of dI2 and dI4 neurons
[30,31]. Interestingly, the correct numbers of dI3
and dI5 neurons that are generated might require the
later function of the bHLH protein Ngn2, the expression
of which spans the dI2–dI5 region [30]. Although functionally downstream of Mash1, how Ngn2 interacts with
Mash1 to generate appropriate numbers of dI3 and dI5
neurons remains unclear. A surprising feature of the
Mash1 knockout phenotype is that dI4s are increased
in the mutants but not as a result of the conversion of
presumptive dI3 and dI5s to dI4 fates. Why this is the case
is not known and awaits further identification of molecular determinants of ventrally located dI4 subtypes.
The development of dI3 and dI5 neurons is particularly
interesting as they are differentially dependent upon
TGFb signals for their generation, but both derive from
Mash1 expressing progenitors (Figure 1b). Expression
analysis of the early patterning HD proteins Gsh1 and
Gsh2 reveals that dI3 neurons express Gsh2, whereas
dI4–5 neurons co-express Gsh1 and Gsh2 [31]. In Gsh2
mutants, dI3 neurons are selectively ablated with a concomitant increase in dI2s, whereas dI4–dI6 neurons
develop normally (Figure 2d). The increase in dI2 subtypes at the expense of dI3s is attributed to the ventral
expansion of the dI2 determinant Ngn1 [29] within the
presumptive dI3 domain, given that Ngn1 is capable of
promoting the differentiation of dI2 subtypes and repressing Mash1 expression [31]. Thus, Gsh2 appears to
function downstream of TGFb signals by repressing
Ngn1 and, therefore, enabling the expression of the
dI3 determinant Mash1 in presumptive dI3 progenitors.
Analysis of Gsh1 and Gsh2 mutants suggest that Gsh1 and
Gsh2 might have redundant functions in the generation of
dI4 and dI5 fates but how this occurs is not clear [31]. In
www.sciencedirect.com
addition to defining roles for bHLH and HD proteins in
dI generation, these studies are beginning to uncover a
possible transcription factor code for dI neuronal specification.
Conclusions and future directions
The large number of signaling molecules implicated in
dorsal patterning promises an intricate and complex network of downstream events that mediate dI differentiation. These studies together with previous work highlight
a recurrent theme in neuronal fate determination in the
spinal cord, namely the use of cross-repressive interactions between proteins to establish progenitor domains.
Here, both bHLH proteins and HD proteins are required
for demarcating the expression domains of determinants
of dI subtypes within progenitors and suggest a possible
code for dI neuronal differentiation. Although many of
these analyses focus on dI1–dI3 generation, these studies
also highlight how little is known about the development
of more ventral dI subtypes. The further identification
and characterization of factors that mark dI4–6 progenitors and neurons will greatly assist in understanding how
these classes of neurons develop.
Acknowledgements
We wish to thank members of the Sockanathan lab for helpful discussions
and comments.
References and recommended reading
Papers of particular interest, published within the annual period of
review, have been highlighted as:
of special interest
of outstanding interest
1.
Liu A, Joyner AL: Early anterior/posterior patterning of the
midbrain and cerebellum. Annu Rev Neurosci 2001, 24:869-896.
2.
Price SR, Briscoe J: The generation and diversification of spinal
motor neurons: signals and responses. Mech Dev 2004,
121:1103-1115.
3.
Jessell TM: Neuronal specification in the spinal cord: inductive
signals and transcriptional codes. Nat Rev Genet 2000, 1:20-29.
4.
Shirasaki R, Pfaff SL: Transcriptional codes and the control of
neuronal identity. Annu Rev Neurosci 2002, 25:251-281.
5.
Chizhikov VV, Millen KJ: Roof plate-dependent patterning of the
vertebrate dorsal central nervous system. Dev Biol 2005,
277:287-295.
6.
Lee KJ, Mendelsohn M, Jessell TM: Neuronal patterning by
BMPs: a requirement for GDF7 in the generation of a discrete
class of commissural interneurons in the mouse spinal cord.
Genes Dev 1998, 12:3394-3407.
7.
Lee KJ, Dietrich P, Jessell TM: Genetic ablation reveals that the
roof plate is essential for dorsal interneuron specification.
Nature 2000, 403:734-740.
8.
Millonig JH, Millen KJ, Hatten ME: The mouse Dreher gene
Lmx1a controls formation of the roof plate in the vertebrate
CNS. Nature 2000, 403:764-769.
9.
Muroyama Y, Fujihara M, Ikeya M, Kondoh H, Takada S: Wnt
signaling plays an essential role in neuronal specification of
the dorsal spinal cord. Genes Dev 2002, 16:548-553.
10. Liem KF Jr, Tremml G, Jessell TM: A role for the roof plate and its
resident TGFbeta-related proteins in neuronal patterning in
the dorsal spinal cord. Cell 1997, 91:127-138.
Current Opinion in Neurobiology 2006, 16:20–24
24 Development
11. Hollyday M, McMahon JA, McMahon AP: Wnt expression
patterns in chick embryo nervous system. Mech Dev 1995,
52:9-25.
12. Megason SG, McMahon AP: A mitogen gradient of dorsal
midline Wnts organizes growth in the CNS. Development 2002,
129:2087-2098.
13. Chesnutt C, Burrus LW, Brown AM, Niswander L: Coordinate
regulation of neural tube patterning and proliferation by
TGFbeta and WNT activity. Dev Biol 2004, 274:334-347.
Studies using in ovo electroporation of chick spinal cords show that BMP
and Wnt signaling pathways have separable functions: specifically, BMPs
as morphogens involved in neural patterning and Wnts as mitogens
involved in neuronal growth. Furthermore, BMPs can regulate the expression of components of the Wnt signaling pathway to coordinate neural
patterning and growth in the spinal cord.
14. Chang H, Brown CW, Matzuk MM: Genetic analysis of the
mammalian transforming growth factor-beta superfamily.
Endocr Rev 2002, 23:787-823.
15. Liu Y, Helms AW, Johnson JE: Distinct activities of Msx1 and
Msx3 in dorsal neural tube development. Development 2004,
131:1017-1028.
In this study, the authors suggest that BMP signaling has distinct functions at different times within the dorsal spinal cord. Constitutively active
BMP receptors induce roof plate formation at early stages, whereas they
promote dI specification at later stages. Overexpression studies in the
chick spinal cord suggest that these events might be mediated by Msx1
and Msx3, respectively.
16. Timmer JR, Wang C, Niswander L: BMP signaling patterns the
dorsal and intermediate neural tube via regulation of
homeobox and helix-loop-helix transcription factors.
Development 2002, 129:2459-2472.
17. Wine-Lee L, Ahn KJ, Richardson RD, Mishina Y, Lyons KM,
Crenshaw EB III: Signaling through BMP type 1 receptors is
required for development of interneuron cell types in the dorsal
spinal cord. Development 2004, 131:5393-5403.
The authors find that ablation of BMP receptors, Bmpr1a and Bmpr1b, in
the neural tube results in the loss of dI1 and dI2 subtypes with the
concomitant dorsal expansion of dI3 and dI4 interneurons. Because
dI3 neurons are assigned to the Class A group, which is dependent on
roofplate-derived signals for their development, this study invokes the
possibility that additional signals might be required for dI3 development.
18. Timmer J, Chesnutt C, Niswander L: The Activin signaling
pathway promotes differentiation of dI3 interneurons in the
spinal neural tube. Dev Biol 2005, 285:1-10.
The authors report that overexpression of a constitutively active Activin IB
receptor in chick spinal cords by in ovo electroporation results in a
specific increase of dI3 subtypes.
19. Gross MK, Dottori M, Goulding M: Lbx1 specifies
somatosensory association interneurons in the dorsal spinal
cord. Neuron 2002, 34:535-549.
20. Muller T, Brohmann H, Pierani A, Heppenstall PA, Lewin GR,
Jessell TM, Birchmeier C: The homeodomain factor lbx1
distinguishes two major programs of neuronal differentiation
in the dorsal spinal cord. Neuron 2002, 34:551-562.
21. Pierani A, Brenner-Morton S, Chiang C, Jessell TM: A sonic
hedgehog-independent, retinoid-activated pathway of
neurogenesis in the ventral spinal cord. Cell 1999, 97:903-915.
Current Opinion in Neurobiology 2006, 16:20–24
22. Novitch BG, Wichterle H, Jessell TM, Sockanathan S: A
requirement for retinoic acid-mediated transcriptional
activation in ventral neural patterning and motor neuron
specification. Neuron 2003, 40:81-95.
23. Diez del Corral R, Olivera-Martinez I, Goriely A, Gale E, Maden M,
Storey K: Opposing FGF and retinoid pathways control ventral
neural pattern, neuronal differentiation, and segmentation
during body axis extension. Neuron 2003, 40:65-79.
24. Sockanathan S, Perlmann T, Jessell TM: Retinoid receptor
signaling in postmitotic motor neurons regulates rostrocaudal
positional identity and axonal projection pattern. Neuron 2003,
40:97-111.
25. Sockanathan S, Jessell TM: Motor neuron-derived retinoid
signaling specifies the subtype identity of spinal motor
neurons. Cell 1998, 94:503-514.
26. Wilson L, Gale E, Chambers D, Maden M: Retinoic acid and the
control of dorsoventral patterning in the avian spinal cord.
Dev Biol 2004, 269:433-446.
By comparing vitamin A-deficient and normal quail embryos, the authors
observe the reduction of dorsal patterning genes and an expansion of
ventral patterning genes in the absence of retinoic acid.
27. Muller T, Anlag K, Wildner H, Britsch S, Treier M, Birchmeier C:
The bHLH factor Olig3 coordinates the specification of dorsal
neurons in the spinal cord. Genes Dev 2005, 19:733-743.
This paper identifies Olig3 as the first class-specific progenitor marker in
the dorsal spinal cord. All Class A neurons derive from Olig3+ progenitors.
In Olig3 knockouts, dI1 interneurons are reduced, whereas dI2 and dI3
subtypes are lost. Olig3 appears to have a dual role in suppressing Class
B identities in dorsal cells and instructing dI3 specification.
28. Helms AW, Johnson JE: Progenitors of dorsal commissural
interneurons are defined by MATH1 expression.
Development 1998, 125:919-928.
29. Gowan K, Helms AW, Hunsaker TL, Collisson T, Ebert PJ, Odom R,
Johnson JE: Crossinhibitory activities of Ngn1 and Math1 allow
specification of distinct dorsal interneurons. Neuron 2001,
31:219-232.
30. Helms AW, Battiste J, Henke RM, Nakada Y, Simplicio N,
Guillemot F, Johnson JE: Sequential roles for Mash1 and Ngn2
in the generation of dorsal spinal cord interneurons.
Development 2005, 132:2709-2719.
The authors investigated the roles of Mash1 and Ngn2 in the generation of
dI3–5 dorsal subtypes. In Mash1 knockout mice, dI3 and dI5 subtypes are
dramatically reduced and neighboring dI2 and dI4–6 neurons are significantly increased. Conversely, in Ngn2 knockouts, dI3 and dI5 showed
subtle increases, whereas other neuronal subtypes remained unaffected.
Further experiments suggest that Mash1 is required for dI3 and dI5
development, whereas Ngn2 might function later to regulate the numbers
of dI3 and dI5 neurons.
31. Kriks S, Lanuza GM, Mizuguchi R, Nakafuku M, Goulding M: Gsh2
is required for the repression of Ngn1 and specification of
dorsal interneuron fate in the spinal cord. Development 2005,
132:2991-3002.
The authors found that in the mouse spinal cord, dI3 progenitors express
Gsh2, whereas dI4 and dI5 progenitors co-express Gsh2 and Gsh1. DI3
development is impaired in Gsh2 knockout mice, whereas dI2 neurons are
increased as a result of expanding Ngn2 expression. Although dI4 and dI5
subtypes also express Gsh2, these neurons were not affected by the loss of
Gsh2, possibly because of the redundant functions of Gsh1 and Gsh2.
www.sciencedirect.com